Project Summary E-cigarette or Vaping Associated Lung Injury (EVALI) is a severe, life-threatening lung disease with16% of cases occurring in patients less than 18 year of age. Unfortunately, over 10% of high school students vape nicotine or THC daily, and nearly 30% of adolescents have vaped in the last month. Given the recent discovery of this disease, we lack crucial information regarding mechanistic pathways of injury, physiologic characteristics, or the long-term health effects of EVALI, particularly in adolescents. It is also unclear if the pathobiology or outcomes of adolescents with EVALI are different than patients who have lung injury triggered by more common causes, such as pneumonia or sepsis. While EVALI represents the most severe form of injury related to e-cigarettes, other significant health consequences from primary or secondary exposure to e-cigarettes or vaping likely exist. E-cigarette exposure is associated with asthma and other respiratory disease, increased airway resistance, and changes in lung function. Nicotine, a component of both combustible and e-cigarettes, has a direct effect on lung and brain development for children and adolescents. There are limited data regarding secondary exposure to e- cigarettes, although they suggest adverse health outcomes. Therefore, there is strong biological plausibility that children and adolescents with primary or secondary e-cigarette exposure will be more susceptible to severe lung injury and adverse health outcomes when they develop lung injury from other causes, such as pneumonia or sepsis. No studies have evaluated this specifically, or whether there is a differential impact of primary or secondary exposure to vaping as a function of age or pre-existing cardio-respiratory comorbidities. We are currently enrolling a cohort of children (< 19 years) admitted to the intensive care unit (ICU) with lung injury and testing whether a ventilator management strategy improves outcomes. We have begun to collect detailed e-cigarette and cigarette exposure history from all participants and have discovered several cases of EVALI. Furthermore, we anticipate nearly 20% of children have significant secondary exposure to e- cigarettes. We will leverage the existing physiologic and outcome data being collected as part of this randomized controlled trial, and combine it with biomarker and RNA sequencing data, and serial 2-year follow- up of pulmonary, neurocognitive, emotional health, and quality of life of all patients who survive to ICU discharge. This will provide an unprecedented opportunity to: (a) understand mechanistic pathways which may be important in the pathogenesis of EVALI, (b) measure the long-term health effects of EVALI in children and adolescents, (c) discover if secondary exposure to e-cigarettes increases susceptibility to more severe disease or poor outcome when children develop lung injury from other causes like pneumonia or sepsis, and (d) determine if continued exposure to e-cigarettes influences the trajectory of recovery.